The American Academy of Pediatrics and the American Academy of Clinical Endocrinology define short stature based on height as more than two standard deviations below the average height of the population. A child with short stature is shorter than approximately 97.5% of children of a similar age and gender and typically attains final adult heights of no more than approximately 5′4″ for boys and 4′11″ for girls. It is estimated that 380,000 children in the U.S. are referred to pediatric endocrinologists for evaluation for short stature.
Children with short stature who are referred for evaluation and possible treatment continue to pose a dilemma for specialists despite decades of dedicated research. For patients with no demonstrable cause for their growth failure, a workup usually ensues which first seeks to differentiate between normal variation, in which the child should reach an adult height concordant with that of the child's genetic potential based on the average height of the parents, and pathologic conditions. In cases of marked short stature, in which the predicted adult height is also low, it is accepted practice to test the status of the growth hormone (GH)-insulin-like growth factor (IGF) axis.
Patients with abnormalities in the GH-IGF axis have a number of possible etiologies. They can present with GH deficiency (GHD), at times attributable to congenital or acquired central nervous system (CNS) lesions affecting the hypothalamus or pituitary, which is almost invariably accompanied by low IGF-1 levels in children. Alternatively, they can present with “primary IGF-1 deficiency” associated with low IGF-1 levels in the face of normal or elevated GH levels. Because IGF-1 is an essential mediator of GH's statural effects, primary IGF-1 deficiency can have similar clinical outcomes to GH deficiency. Such cases of primary IGF deficiency, in otherwise healthy and well-nourished patients, are likely to be caused by a defect somewhere in the GH-IGF axis downstream from the production or secretion of GH. This type of GH insensitivity or GH resistance is as yet unexplained in most cases, although it has been associated with mutations affecting the extra-cellular domain of the GH receptor in 1-5% of idiopathic short stature (ISS) children and adults, with mutations in Stat5b, with mutations in the acid labile subunit (ALS), or with mutations or polymorphisms in the IGF-1 gene itself.
GH deficiency is well recognized as a disease requiring replacement therapy with GH in children to treat short stature and in adults to correct body composition, bone density, cardiovascular function, and well being. By contrast, low IGF-1 levels, in the presence of normal GH secretion, has been previously usually associated only with a rare disease, recognized as Laron syndrome or growth hormone insensitivity syndrome (GHIS).
Most patients with Laron syndrome or GHIS lack growth hormone receptor binding activity and have absent or very low GH-binding protein (GHBP) activity in blood. Such patients are extremely short and have a mean height standard deviation score (SDS) of about −5 to −6, are resistant to GH treatment, and have increased serum concentrations of GH and low serum concentrations of IGF-1. As children they show a statural growth response to treatment with IGF-1.
The disease of short stature due to partial GH receptor defects was traditionally seen as primarily a disease characterized by a low GHBP level rather than a low IGF-1 level, with IGF-1 levels being only at the low end of the normal range. Specifically, the patient is defined as having a height of at least about 2 standard deviations or more below the normal mean for a corresponding age and gender (at least −2.0 SD below the mean), a serum level of high-affinity growth hormone binding protein that is at least 2 standard deviations below normal mean levels, a serum level of IGF-1 that is below normal mean levels, and a serum level of growth hormone that is at least normal.
The importance of this classification of the various factors affecting short stature is shown in the relative numbers of patients who are: 1) IGF-1 deficient and GH deficient and 2) IGF-1 deficient and GH sufficient. Current literature would predict that many more children and adults would be IGF-1 deficient due to GH deficiency than would be IGF-1 deficient and GH sufficient.
The therapeutic use of IGF-1 is well known and well studied. However, optimal delivery methods for the use of IGF-1 have not been developed. In human therapy, there is debate as to the optimal dose regimen of administration. At present, the accepted mode of delivery is twice daily dosing of IGF-1 in children with complete GH resistance (patients with Laron-type syndrome) or complete GH deficiency (GH gene deletion children). These patient groups have either a complete lack of GH action or a complete lack of the GH protein due to the GH gene being non-functional
However, in patients who are not completely GH deficient or completely GH resistant, there is less information on how to dose with IGF-1 to achieve optimal efficacy. In the study reported by Bucuvalas, et al. {Bucuvalas, 2001 #371}, twice daily IGF-1 dosing was administered to patients with intact GH secretion and relatively normal IGFBP-3 levels. Bucuvalas, et al. used a dose of 80 micrograms IGF-1/kg patient bodyweight, the standard therapeutic dose used to treat children suffering from complete GH resistance. Bucuvalas, et al. found no significant increase in the growth rate of treated children. Bucuvalas, et al. reported that the growth velocity in the treated children was 6.0±1.9, and the growth velocity in the control group was 5.0±1.7, cm/year. Since no statistically significant improvement in growth was reported by Bucuvalas, et al., an effective IGF-1 dosing regimen for growth promotion has yet to be established for patients who are not completely GH resistant or GH deficient. In GH and IGF-1 deficient animals it has been shown that the more frequently rhIGF-1 is injected, the greater the growth response. However there appears to be no data in the literature on the efficacy of rhIGF-1 injection regimens on body growth in animals with intact GH secretion.
Osteoporosis, or porous bone, is a disease characterized by low bone mass and structural deterioration of bone tissue, leading to bone fragility and an increased susceptibility to fractures of the hip, spine, and wrist. It is a devastating disease among both postmenopausal women as well as among older men. The direct medical cost of osteoporosis is currently estimated to be over $13.8 billion per year. Unless interventions are begun immediately, the aging U.S. population will drive this cost up to an estimated $60 billion per year by year 2020. (available on the world wide web at nof.org/advocacy/leg_issue_briefs/Dec—99_advocacy.htm). At present, the mainstays of therapy are oral calcium supplements, vitamin D supplements, and a family of medications termed “anti-resorptives” which reduce osteoclastic bone resorption. These include estrogens, such as conjugated estrogens (Premarin™); selective estrogen receptor modulators (SERMs), such as raloxifene (Evista™); calcitonin (Miacalcin™); and bisphosphonates, such as alendronate (Fosamax™), risedronate (Actonel™), etidronate (Didronel™), pamidronate (Aredia™), tiludronate (Skelid™), or zoledronic acid (Zometa™). See, The writing group for the PEPI trial, JAMA 276: 1389-1396 (1996); Delmas et al., N Engl J Med 337: 1641-1647 (1997); Chestnut et al., Osteoporosis hit 8 (suppl 3): 13 (1998); Liberman et al., N Engl J Med 333: 1437-1443 (1995); McClung et al., N Engl J Med 344: 333-40 (2001). These drugs are effective in slowing bone mineral loss and even cause moderate increases in lumbar spine bone mineral density in the range of 2% (calcium, vitamin D, calcitonin), 3% (raloxifene), 6% (estrogens) or 8% (bisphosphonates). In general, two to three years of administration are required to achieve effects of this magnitude. See, The writing group for the PEPI trial, JAMA 276: 1389-1396 (1996); Delmas et al., N Engl J Med 337: 1641-1647 (1997); Chestnut et al., Osteoporosis Int 8 (suppl 3): 13 (1998); Liberman et al., N Engl J Med 333: 1437-1443 (1995); McClung et al., N Engl J Med 344: 333-40 (2001).
Osteoporosis exists, in general, when skeletal mineral losses result in a bone mass that is in the range of 50% below the peak bone mass. Peak bone mass occurs at approximately age 30. Seen from the perspective of correcting the deficit in bone mineral, complete reversal of this 50% loss would require a 100% increase in bone mass. Thus, the 2-8% increases in bone mineral density which result from anti-resorptive therapy, while clinically significant and beneficial, leaves very significant room for improvement. Since the use of anti-resorptives to prevent bone loss does not result in significant new bone production, the ultimate effectiveness of anti-resorptives in quantitative terms is limited. These considerations emphasize the need for the development of pharmaceutical mechanisms to produce new bone.
Osteoporosis is defined operationally by the National Osteoporosis Foundation and World Health Organization as a bone density that falls −2.0 or −2.5 standard deviations (SD) below the mean for lifetime peak bone density achieved in gender-matched and race-matched normal young adults (aged 20-25 years) (also referred to as a T-score of −2.0 or −2.5). Those who fall at the lower end of the gender-matched and race-matched normal young adult range (a T-score of >1 SD below the mean) have low bone density and are considered to be “osteopenic” and be at increased risk of osteoporosis.
IGF-1 is the primary protein hormone mediating the growth promoting effects of GH on bone. IGF-1 is produced in response to GH and then induces subsequent cellular responses, including cellular responses in bone.
IGF-1 plays a central role in bone formation. During mammalian growth GH induces IGF-1 expression in the liver and the skeleton. This endocrine and local IGF-1 causes bone growth via the epiphyseal growth plate chondrocytes and the expansion of the outer cortical envelope via periosteal osteoblasts. GH-induced expression of IGF-1 in the trabecular compartment of the skeleton may also recruit stromal cells into the bone lineage and the terminal differentiation of endosteal osteoblasts. Therefore in response to GH, each of these three skeletal components (the growth plate, the periosteum, and the endosteum) responds to IGF-1. Finally, this newly formed bone matrix becomes fully mineralized which ends skeletal maturation. Thus, IGF-1 plays a pivotal role in processes that include lifelong bone remodeling in the adult. Therefore, if a human or animal is GH resistant or IGF-1 deficient these processes are slowed so that bone length and statural height are reduced and bone structure compromised. The administration of rhIGF-1 in animals has been shown to correct such deficits in cartilage and bone growth and in bone structure.
Significant bone loss occurs in patients suffering from anorexia nervosa. Furthermore, bone loss is permanent in a significant number of anorexia nervosa patients despite weight recovery. The nutritional stress in patients suffering from anorexia nervosa adversely affects the growth hormone/IGF-1 axis and creates an IGF-1 deficiency that can contribute to severe bone loss in this population.
The administration of rhIGF-1 in mouse models of IGF-1 deficiency has been shown to correct such deficits in cartilage and bone growth and in bone structure Yakar, S., C. J. Rosen, et al., J. Clin. Invest., 110(6): 771-81 (2002). In the ovariectomized rat, a model of osteoporosis, the administration of rhIGF-1 has increased cortical and trabecular bone and increased bone strength in the rat (Ammann, P., R. Rizzoli, et al., Osteoporos. Int., 6(3): 219-27 (1996) (Verhaeghe, J., E. Van Herck, et al., Growth Regul. 5(4): 210-7 (1995)) (Verhaeghe, J., R. van Bree, et al., J. Bone Miner. Res., 11(11): 1723-35 (1996)) (Mueller, K., R. Cortesi, et al., Am. J. Physiol., 267(1 Pt 1): E1-6 (1994)) (Bagi, C., M. van der Meulen, et al., Bone, 16(5): 559-65 (1995)) and in the dog (U.S. Pat. No. 6,358,925).
Grinspoon, et al., “Effects of Recombinant Human IGF-1 and Oral Contraceptive Administration on Bone Density in Anorexia Nervosa,” J. Clin. Endo. Metab., 87: 2883-2891 (2002) reported the results of a clinical study of IGF-1 therapy in patients suffering from anorexia nervosa and bone loss characterized by osteopenia and/or osteoporosis. The study results indicated that (i) IGF-1 monotherapy prevented a loss of bone mineral density and (ii) IGF-1/estrogen combination therapy achieved an increase in bone mineral density compared to pre-treatment baseline values in patients suffering from anorexia nervosa and bone loss.
Cachexia is a multi-factorial disease of increased neurohormonal activity and immune abnormalities, resulting in hormonal and metabolic catabolic/anabolic imbalance of the body, leading to the loss of fat and lean mass and ultimately death. The physiological, metabolic, and behavioral changes in cachexia are associated with patient complaints of weakness, fatigue, gastrointestinal distress, sleep/wake disturbances, pain, listlessness, shortness of breath, lethargy, depression, malaise and the fear of being a burden on family and friends. Although cachexia has been classically associated with chronic diseases such as heart failure, termed cardiac cachexia, infections and malignant conditions, it has also been identified in patients after extensive traumatic injury and sepsis, and in aging persons with failure to thrive syndrome.
Muscle cachexia, mainly reflecting degradation of myofibrillar proteins, is an important clinical feature in cachectic patients. A redistribution of the body's protein content occurs, with preferential depletion of skeletal muscle and an increase in the synthesis of proteins involved in the response to tissue injury. Muscle cachexia is associated with increased gene expression and activity of the calcium/calpain and ubiquitin/proteasome-proteolytic pathways. Calcium/calpain-regulated release of myofilaments from the sarcomere is an early, and perhaps rate-limiting, component of the catabolic response in muscle. Understanding the mechanisms regulating muscle protein breakdown is important for the development of therapeutic strategies aimed at preventing and managing muscle cachexia. The catabolic response in skeletal muscle may result in muscle wasting and weakness that has important clinical implications such as difficulty with ambulation, impaired rehabilitation and increased risk for pulmonary complications.
The cachexia-anorexia syndrome involves metabolic pathology and is associated with hypertriacylglycerolemia, lipolysis, and acceleration of protein turnover. These changes result in the loss of fat mass and body protein. Increased resting energy expenditure in weight-losing cachectic patients can occur despite the reduced dietary intake, indicating systemic dysregulation of host metabolism. Cachexia, regardless of the underlying diagnosis, can rarely be explained by the actual energy and substrate demands or by the diagnosis itself. Cachexia involves immune changes, and cytokines have been identified in the development and/or progression of the cachexia-anorexia syndrome. For example, interleukin-1, interleukin-6 (and its subfamily such as ciliary neurotrophic factor and leukemia inhibitory factor), interferon-gamma, tumor necrosis factor-alpha, and brain derived neurotrophic factor have been associated in various cachectic conditions.
It is the object of this invention to show that there are unexpected differences in the responses of various patient groups to various IGF-1 treatment modalities. An optimal dose-regimen is disclosed for stimulating growth using IGF-1.
In addition, from reports of the co-administration of IGF-1 and GH, K-O mouse data and biochemical evidence it appears there are synergistic or greater than additive effects of the combination of GH and IGF-1. It is an object of this invention to demonstrate how with the administration of IGF-1 that this synergism or greater than additive activity can be maintained or enhanced utilizing the GH that is endogenously produced. Another object of the invention is to show that with certain modes and injection schemes of IGF-1 that endogenous GH secretion can be preserved or enhanced and so GH activity can be preserved and synergy or greater than additive activity due to the combination of GH and IGF-1 can be maintained or enhanced.
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